PMID- 34219361
OWN - NLM
STAT- MEDLINE
DCOM- 20211102
LR  - 20220721
IS  - 1478-3231 (Electronic)
IS  - 1478-3223 (Print)
IS  - 1478-3223 (Linking)
VI  - 41
IP  - 11
DP  - 2021 Nov
TI  - PPAR-gamma-induced changes in visceral fat and adiponectin levels are associated with 
      improvement of steatohepatitis in patients with NASH.
PG  - 2659-2670
LID - 10.1111/liv.15005 [doi]
AB  - BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor (PPAR)-gamma agonists 
      decrease hepatic/visceral fat (VF) and improve necroinflammation despite 
      subcutaneous (SC) fat weight-gain. Understanding the impact of changes in VF, 
      VF-to-SC fat distribution (VF/SC) and adiponectin (ADPN) levels in relation to 
      histological improvement after weight-loss or pioglitazone is relevant as novel 
      PPAR-gamma agonists are being developed for treating non-alcoholic steatohepatitis 
      (NASH). METHODS: Fifty-five patients with NASH received a -500 kcal/d hypocaloric 
      diet and were randomized (double-blind) to pioglitazone (45 mg/d) or placebo for 
      6-months. Before and after treatment patients underwent a liver biopsy and 
      measurement of hepatic/peripheral glucose fluxes, hepatic/adipose tissue-IR and, 
      in 35 patients, hepatic and VF/SC-fat was measured by magnetic resonance 
      spectroscopy/imaging. Data were examined by multivariable statistical analyses 
      combined with machine-learning techniques (partial least square discriminant 
      analysis [PLS-DA]). RESULTS: Both pioglitazone (despite weight-gain) and placebo 
      (if weight-loss) reduced steatosis but only pioglitazone ameliorated 
      necroinflammation. Using machine-learning PLS-DA showed that the treatment 
      differences induced by a PPAR-gamma agonist vs placebo on metabolic variables and 
      liver histology could be best explained by the increase in ADPN and a decrease in 
      VF/SC, and to a lesser degree, improvement in oral glucose tolerance test-glucose 
      concentrations and ALT. Decrease in steatosis and disease activity score 
      (ballooning plus lobular inflammation) kept a close relationship with an increase 
      in ADPN (r = -.71 and r = -.44, P < .007, respectively) and reduction in VF/SC 
      fat (r = .41 and r = .37, P < .03 respectively). CONCLUSIONS: Reduction in VF and 
      improved VF/SC-distribution, combined with an increase in ADPN, mediate the 
      histological benefits of PPAR-gamma action, highlighting the central role of fat 
      metabolism and its distribution on steatohepatitis disease activity in patients 
      with NASH.
CI  - (c) 2021 The Authors. Liver International published by John Wiley & Sons Ltd.
FAU - Gastaldelli, Amalia
AU  - Gastaldelli A
AUID- ORCID: 0000-0003-2594-1651
AD  - Diabetes Division, The University of Texas Health Science Center at San Antonio, 
      San Antonio, TX, USA.
AD  - Institute of Clinical Physiology, National Research Council, CNR, Pisa, Italy.
FAU - Sabatini, Silvia
AU  - Sabatini S
AUID- ORCID: 0000-0003-3251-4412
AD  - Institute of Clinical Physiology, National Research Council, CNR, Pisa, Italy.
AD  - Universita degli Studi di Siena, Siena, Italy.
FAU - Carli, Fabrizia
AU  - Carli F
AUID- ORCID: 0000-0003-2540-1110
AD  - Institute of Clinical Physiology, National Research Council, CNR, Pisa, Italy.
FAU - Gaggini, Melania
AU  - Gaggini M
AUID- ORCID: 0000-0002-6311-502X
AD  - Institute of Clinical Physiology, National Research Council, CNR, Pisa, Italy.
FAU - Bril, Fernando
AU  - Bril F
AUID- ORCID: 0000-0001-5570-4396
AD  - Division of Endocrinology, Diabetes and Metabolism, University of Florida, 
      Gainesville, FL, USA.
FAU - Belfort-DeAguiar, Renata
AU  - Belfort-DeAguiar R
AUID- ORCID: 0000-0002-4357-0447
AD  - Department of Internal Medicine and Endocrinology, Yale University School of 
      Medicine, New Haven, CT, USA.
FAU - Positano, Vincenzo
AU  - Positano V
AUID- ORCID: 0000-0001-6955-9572
AD  - Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
FAU - Barb, Diana
AU  - Barb D
AUID- ORCID: 0000-0001-5208-6828
AD  - Division of Endocrinology, Diabetes and Metabolism, University of Florida, 
      Gainesville, FL, USA.
FAU - Kadiyala, Sushma
AU  - Kadiyala S
AD  - Division of Endocrinology, Diabetes and Metabolism, University of Florida, 
      Gainesville, FL, USA.
AD  - Division of Endocrinology, Diabetes and Metabolism, Malcom Randall Veteran 
      Administration Medical Center at Gainesville, Gainesville, FL, USA.
FAU - Harrison, Stephen
AU  - Harrison S
AUID- ORCID: 0000-0001-8285-2204
AD  - Pinnacle Clinical Research Group, San Antonio, TX, USA.
FAU - Cusi, Kenneth
AU  - Cusi K
AUID- ORCID: 0000-0002-8629-418X
AD  - Division of Endocrinology, Diabetes and Metabolism, University of Florida, 
      Gainesville, FL, USA.
AD  - Division of Endocrinology, Diabetes and Metabolism, Malcom Randall Veteran 
      Administration Medical Center at Gainesville, Gainesville, FL, USA.
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20210721
PL  - United States
TA  - Liver Int
JT  - Liver international : official journal of the International Association for the 
      Study of the Liver
JID - 101160857
RN  - 0 (Adiponectin)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (PPAR gamma)
RN  - 0 (Thiazolidinediones)
SB  - IM
MH  - Adiponectin
MH  - Diet, Reducing
MH  - Humans
MH  - Hypoglycemic Agents/therapeutic use
MH  - *Insulin Resistance
MH  - Intra-Abdominal Fat
MH  - Liver
MH  - *Non-alcoholic Fatty Liver Disease/drug therapy
MH  - Obesity
MH  - PPAR gamma
MH  - *Thiazolidinediones/therapeutic use
PMC - PMC9290929
OTO - NOTNLM
OT  - NASH
OT  - PPAR-y
OT  - adiponectin
OT  - fatty liver
OT  - insulin resistance
OT  - pioglitazone
OT  - type 2 diabetes mellitus
OT  - visceral fat
COIS- S.S, CF, GM, FB, RA, PV, DB, SK have nothing to disclose. AG has received 
      honorarium from Novo Nordisk and is consultant for Boehringer Ingelheim, Eli 
      Lilly, Gilead, Inventiva, and Pfizer. KC has received research support as 
      principal investigator for the University of Florida from the National Institute 
      of Health (NIH), Cirius, Echosens, Inventiva, Novartis, Novo Nordisk, Poxel and 
      Zydus. KC is also a consultant for Allergan, Altimmune, Arrowhead, AstraZeneca, 
      BMS, Boehringer Ingelheim, Coherus, Eli Lilly, Fractyl, Hanmi, Genentech, Gilead, 
      Intercept, Janssen, Pfizer, Prosciento, Madrigal and Novo Nordisk. SAH: 
      Scientific advisor or consultant for Akero, Alentis, Altimmune, Arrowhead, 
      Axcella, Canfite, Cirius, CiVi Biopharma, Cymabay, Echosens, Fibronostics, Forest 
      Labs, Galectin, Genfit, Gilead, Hepion, HistoIndex, Intercept, Madrigal, Medpace, 
      Metacrine, NGM Bio, Northsea, Novartis, Novo Nordisk, PathAI, Poxel, Liminal, 
      Ridgeline, Sagiment, Terns, Viking, 89 Bio. Stock options: Akero, Cirius, 
      Galectin, Genfit, Hepion, HistoIndex, PathAI, Metacrine, NGM Bio, Northsea. 
      Grant/Research support: Akero, Axcella, BMS, Cirius, CiVi Biopharma, Conatus, 
      Cymabay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, Intercept, 
      Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, Northsea, Pfizer, Sagimet, 
      Viking.
EDAT- 2021/07/06 06:00
MHDA- 2021/11/03 06:00
PMCR- 2022/07/18
CRDT- 2021/07/05 05:48
PHST- 2021/06/22 00:00 [revised]
PHST- 2021/04/17 00:00 [received]
PHST- 2021/06/24 00:00 [accepted]
PHST- 2021/07/06 06:00 [pubmed]
PHST- 2021/11/03 06:00 [medline]
PHST- 2021/07/05 05:48 [entrez]
PHST- 2022/07/18 00:00 [pmc-release]
AID - LIV15005 [pii]
AID - 10.1111/liv.15005 [doi]
PST - ppublish
SO  - Liver Int. 2021 Nov;41(11):2659-2670. doi: 10.1111/liv.15005. Epub 2021 Jul 21.